Prostate cancer is the most common internal malignancy and second leading cause of cancer mortality among U.S. men. The androgen pathway in the prostate is believed to mediate carcinogenesis by stimulating cell proliferation, thereby increasing the opportunity for random genetic errors to accumulate and give rise to a malignant phenotype. Androgen activity in the prostate is regulated by enzymes and transcription factors that are encoded by highly polymorphic genes. We propose to test the hypothesis that the possession of certain variant alleles in genes in the androgen pathway increases a man's risk of prostate cancer. Specifically the genes of interest encode: (1) steroid 5 alpha-reductase type II (SRD5A2), which bioactivates androgens in the prostate; (2) androgen receptor (AR), an androgen-dependent nuclear transcription factor; and (3) prostate-specific antigen (PSA), a serine protease transactivated by AR that cleaves and reverses the growth-inhibitory effects of insulin-like growth factor binding protein-3 (IGFBP-3). The SRDSA2, AR, and PSA genes each encode products that mediate androgen stimulation of the prostate. Furthermore, each gene possesses a polymorphism with demonstrated functionality and sufficient allelic frequency to explain a substantial proportion of prostate cancer in the U.S. population. We propose to conduct a nested case-control study within the Cardiovascular Health Study (CHS) to test the hypothesis that possession of variant alleles in the SRDSA2, AR, and PSA genes, individually and in combination, increases a man's risk of prostate cancer. CHS is a multicenter cohort study in older adults that has prospectively collected detailed interview data and blood samples since 1989. Cases will be approximately 210 CHS male participants diagnosed with prostate cancer after enrollment and through 1999. Controls will be 420 CHS male participants, frequency matched to cases by age and race, who were not diagnosed with prostate cancer through 1999 and who were alive as of the date of diagnosis of the matched case. We propose to conduct laboratory analysis of DNA samples provided by CHS to determine the presence of variant alleles among cases and controls, and statistical analysis to assess whether SRD5A2, AR, and PSA genotypes influence the risk of prostate cancer. The identification and confirmation of high-risk genetic profiles for prostate cancer could enable better screening and potential preventive interventions aimed at the gene products.